Use of coumarin derivatives for the preparation of drugs for treating skin diseases

ABSTRACT

A compound of formula (I-1) 
     
       
         
         
             
             
         
       
     
     wherein n equals 0 or 1, Z represents O or S, R1 represents one group chosen among the group consisting of hydrogen, C1-C7 alkyl, substituted, or not, by a halogen, a hydroxyl or a —O—R12 group, wherein R12 is a C1-C7 alkyl, a group —CH 2 —O—CO—R5 wherein R5 is chosen among a hydrogen atom and a C1-C7 alkyl, substituted or not by at least one halogen, a group —O—R13, wherein R13 is chosen among hydrogen and a C1-C7 alkyl, an amine or a —CH 2 -amine, R′1 represents a group chosen among hydrogen and —O—R14, wherein R14 is chosen among hydrogen and a C1-C7 alkyl, and R2 is chosen among the group consisting of a C1-C7 alkyl, a C3-C6 cycloalkyl, an aryl group, and an heteroaryl group for the treatment of pathologies involving excess activity of at least one member of the kallikrein family.

The invention relates to the use of coumarin derivatives for thepreparation of drugs for treating skin diseases.

Coumarin is a benzopyran found in many plants. It was first synthesizedby William H. Perkin in 1868 (W. H. Perkin, J. Chem. Soc. 1868, 21, p53) and its first use in perfumes since 1882 is due to its sweet odor,readily recognised as the scent of sweet grass and sweet clover. In thepharmaceutical industry, coumarin and other benzopyrans have numerousapplications (Riveiro, M. E., De Kimpe, N., Moglioni A., Vasquez, R.,Monczor, F., Shayo, C., Davio, C. Curr. Med. Chem., 2010, 17(13),1525-38; Wu, L., Wang, X., Xu, W., Farzaneh, F., Xu, R., Curr. Med.Chem, 2009, 16(32), 4236-60). For example, some derivatives are known asantitumoral compounds (Liu, X. H., Liu, H. F., Chen, J., Yang, Y., Song,B. A., Bai, L. S., Liu, J. X., Zhu, H. L., and Qi, X. B., Bioorg MedChem Lett, 2010, 20, 5705-5708; Maresca, A., Temperini, C., Vu, H.,Pham, N. B., Poulsen, S. A., Scozzafava, A., Quinn, R. J., and Supuran,C. T., J Am Chem Soc, 2009, 131, 3057-3062; Maresca, A., and Supuran, C.T. Bioorg Med Chem Lett, 2010, 20, 4511-4514; Star{hacek over (c)}evićS, Kocbek P, Hribar G, Lani{hacek over (s)}nik Ri{hacek over (z)}ner T,Gobec S. Chem Biol Interac. 2011, 191(1-3):60-5, as neuroprotectorcompounds (Liu, W. B., Zhou, J., Qu, Y, Li, X., Lu, C. T., Xie, K. L.,Sun, X. L., and Fei, Z., Neurochem Int, 2010, 57, 206-215), asantibacterial compounds (Parvez, A., Meshram, J., Tiwari, V., Sheik, J.,Dongre, R., Youssoufi, M. H., and Ben Hadda, T. Eur J Med Chem, 2010,45, 4370-4378), as anti-Alzheimer compounds (Pisani, L., Catto, M.,Giangreco, I., Leonetti, F., Nicolotti, O., Stefanachi, A., Cellamare,S., and Carotti, A., Chem Med Chem, 2010, 5, 1616-1630; Fallarero, A.,Oinonen, P., Gupta, S., Blom, P., Galkin, A., Mohan, C. G, and Vuorela,P. M., Pharmacol Res, 2008, 58, 215-221; Shelton, C. C., Zhu, L., Chau,D., Yang, L., Wang, R., Djaballah, H., Zheng, H., and Li, Y. M. ProcNatl Acad Sci USA, 2009, 106, 20228-20233), anti-VIH compounds (Huang,L., Yuan, X., Yu, D., Lee, K. H., and Chen, C. H., Virologyl, 2005, 332,623-628.; Yu, D., Suzuki, M., Xie, L., Morris-Natschke, S. L., and Lee,K. H. Med Res Rev, 2003, 23, 322-345).

Coumarin derivative compounds are already known as serine proteaseinhibitors (WO9855472; Pochet L., Doucet C., Schynts M., Thierry N.,Boggetto N., Pirotte B., Jiang K. I., Masereel B., de Tullio P., DelargeJ., Reboud-Ravaux M., J. Med. Chem, 1996, 39, 2579-2585; Doucet C.,Pochet L., Thierry N., Pirotte B., Delarge J., Reboud-Ravaux M., J. Med.Chem, 1999, 42, 4161-4171).

Some of the compounds used in this patent definitively inactivate theα-chymotrypsin whereas human leukocyte elastase and human thrombin aretemporarily inactivated.

Among the skin pathologies, Netherton syndrome (Comel C., <<Ichtyosislinearis circumflexa, Dermatologica, 1949, 98, 133-136; Netherton E. W.,<<a unique case of trichorrexis invaginata>>, Arch Dermatol, 1958, 78,483-487; Hovnanian A. et al, Mol Biol Cell, 2007, 18, 3607-3619;Hovnanian A. et al, Nat Med, 2007, 13, 975-80; Hovnanian A. et al, NatGenet, 2005, 37, 56-65; Hovnanian A. et al, Nat Genet, 2000, 25,141-142; Hovnanian A. et al, J. Clin. Invest, 2010, 120871-120882), isan inherited disease caused by a genetic abnormality in one chromosome.It entails abnormal skin desquamation and inflammatory phenomenons.Babies born with the syndrome have red and scaly skin, which can easilyget infected, and they fail to thrive in their first years of life. Theyalso have abnormal ‘bamboo-type’ hair. Netherton syndrome is a long-termdebilitating and life-threatening condition because of the skininfections associated with the changes of the physical appearance of thepatients and effects on the patients' mental state.

At the time of designation, Netherton syndrome affected approximately0.05 in 10,000 people in the European Union.

There is no known cure at the moment for the Netherton syndrome, onlyseveral things can be done such as relieving the symptoms. Moisturisingproducts are very helpful to minimise the scaling/cracking andanti-infective treatments are useful when appropriate because the skinis very susceptible to infection. Steroids can also be used.

This skin pathology may appear if the endogenous protein inhibitor LEKTI(lympho-epithelial Kazal type inhibitor) which controls the activity ofa specific kind of serine protease belonging to the kallikrein family,is not active (Chavanas S., Bodemer C., Rochat A., Hamel-Teillac D., AliM., Irvine A. D., Nat Genet 2000, 25, 141-142; Deraison C., Bonnart C.,Lopez E, Besson C., Robinson R., Jayakumar A., Mol Biol Cell, 2007, 18,3607-3619).

One of the aim of the invention is to provide coumarin derivatives ableto treat skin diseases, in particular orphan skin diseases.

One of the aim of the invention is to provide pharmaceuticalcompositions for the treatment of pathologies involving an excess ofactivity of at least one member of the kallikrein family, in particularkallikrein-5 (KLK5), kallikrein-7 (KLK7) or kallikrein-14 (KLK14).

Another aim of the invention is to provide prevention or treatment ofskin pathologies consisting of Netherton syndrome and atopic dermatitis,eczema, peeling skin syndrome, psoriasis, in particular Nethertonsyndrome.

Thus, the present invention relates to compounds of formula (I) aspresented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br, and        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl or an hetero aryl substituted            by one linear or branched, saturated or not, C1-C7 alkyl,            said aryl or heteroaryl is also substituted by at least            another group, which is different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

By the expression “if R1≠H, then if R2 is an aryl or an hetero arylsubstituted by one linear or branched, saturated or not, C1-C7 alkyl,said aryl or heteroaryl is also substituted by at least another groupdifferent from a C1-C7 alkyl” is meant that if n=1, and if R1 isdifferent from hydrogen and if R2 is an aryl or an hetero arylsubstituted by one linear or branched, saturated or not, C1-C7 alkyl,then R2 has to be substituted by at least another group different from aC1-C7 alkyl.

The kallikreins were first named by E. Werle who reported in 1934finding a substance in the pancreas of men and various animals in suchgreat amounts that the pancreas could be taken for its site of origin.He named it kallikrein, by derivation from the Greek word for pancreas.It is clear that the fifteen known kallikreins are serine proteases withsufficient structural and functional similarities to be classified as afamily.

Among the different members of this family of serine proteases, thefocus is on kallikreins named KLK5, KLK7, KLK14, which are involved inskin desquamation and inflammatory phenomenons.

The present invention also relates to compounds of formula (I) aspresented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br, and        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            naphthyl, or a phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl different from a naphthyl, or            an hetero aryl, substituted by one linear or branched,            saturated or not, C1-C7 alkyl, said aryl or heteroaryl is            also substituted by at least another group, which is            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

The present invention also relates to compounds of formula (I-1) aspresented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen, provided that R′1 represents hydrogen        when R1 does not represent a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl or an hetero aryl substituted            by one linear or branched, saturated or not, C1-C7 alkyl,            said aryl or heteroaryl is also substituted by at least            another group different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

The present invention also relates to compounds of formula (I-1) aspresented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen, provided that R′1 represents hydrogen        when R1 does not represent a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            naphthyl, or a phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl different from a naphthyl, or            an hetero aryl, substituted by one linear or branched,            saturated or not, C1-C7 alkyl, said aryl or heteroaryl is            also substituted by at least another group, which is            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds wherein said pathologies are skin pathologies.

The use of the coumarin derivatives of the invention may be a way fortreating skin pathologies involving an excess of activity of at leastone member of the kallikrein family, belonging to the group consistingof KLK5, KLK7 and KLK14.

The activation cascade involving these kallikreins is represented inFIG. 1.

According to another embodiment, the present invention relates to theabove mentioned compounds wherein said pathologies belong to the groupconsisting of Netherton syndrome, atopic dermatitis, psoriasis, eczemaand peeling skin syndrome, preferably Netherton syndrome.

According to another embodiment, the present invention relates to theabove mentioned compounds wherein said pathologies belong to the groupconsisting of Netherton syndrome, psoriasis, atopic eczema and allergiccontact dermatitis, preferably Netherton syndrome.

Netherton syndrome, inherited skin disease, is caused by a geneticabnormality. The SPINK5 chromosome is responsible for LEKTI enzymeinhibitor (Chavanas S., Bodemer C., Rochat A., Hamel-Teillac D., Ali M.,Irvine A. D., <<Mutations in SPINK5, encoding a serine proteaseinhibitor, cause Netherton syndrom>>, Nat Genet 2000, 25, 141-142;Magert H. J., Standker L., Kneutzmann P., “LEKTI, a novel 15-domain typeof human serine proteinase inhibitor, J Biol Chem, 1999, 274,21499-21502; Deraison C., Bonnart C., Lopez E, Besson C., Robinson R.,Jayakumar A., <<LEKTI fragments specifically inhibit KLK5, KLK7 andKLK14 and control desquamation through a pH-dependent interaction>>, MolBiol Cell, 2007, 18, 3607-3619).

According to another embodiment, the present invention relates to theabove mentioned compounds wherein said at kallikrein family memberprotein is chosen among the group consisting of kallikrein-5,kallikrein-7 and kallikrein-14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (Ia):

wherein

R1 represents a linear or branched, saturated or not, C1-C7 alkyl,preferably a methyl group, possibly substituted by a halogen, and

R2 represents a methyl group, a cycloalkyl or an aryl group, preferablya cyclohexyl or a phenyl group.

According to another embodiment, the present invention relates to theabove mentioned compound:

-   -   In this case, in the general formula, n=0.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (Ib):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   a hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br, and        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, Cl-05 alkyl,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   if R1=H, then R2 can only represent an isoquinolinyl or a phenyl        substituted by two halogens, and

    -   if R1≠H, if R2 is an aryl or an hetero aryl substituted by one a        linear or branched, saturated or not, C1-C7 alkyl, said aryl or        heteroaryl is also substituted by at least another group        different from a C1-C7 alkyl.

    -   In this case, in the general formula, n=1, Z being oxygen or        sulfur atom.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (Ib):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   a hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br, and        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   if R1=H, then R2 can only represent an isoquinolinyl or a        naphthyl, or a phenyl substituted by two halogens, and

    -   if R1≠H, then if R2 is an aryl different from a naphthyl, or an        hetero aryl, substituted by one linear or branched, saturated or        not, C1-C7 alkyl, said aryl or heteroaryl is also substituted by        at least another group, which is different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-1b):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen, provided that R′1 represents hydrogen        when R1 does not represent a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   if R1=H, then R2 can only represent an isoquinolinyl or a phenyl        substituted by two halogens, and

    -   if R1≠H, if R2 is an aryl or an hetero aryl substituted by one a        linear or branched, saturated or not, C1-C7 alkyl, said aryl or        heteroaryl is also substituted by at least another group        different from a C1-C7 alkyl.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-1b):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen, provided that R′1 represents hydrogen        when R1 does not represent a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   if R1=H, then R2 can only represent an isoquinolinyl or a        naphthyl, or a phenyl substituted by two halogens, and

    -   if R1≠H, then if R2 is an aryl different from a naphthyl, or an        hetero aryl, substituted by one linear or branched, saturated or        not, C1-C7 alkyl, said aryl or heteroaryl is also substituted by        at least another group, which is different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14.

The present invention also relates to compounds of formula (I-h1) aspresented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that    -   when n=0, R2 is a methyl group or a cycloalkyl group, preferably        a cyclohexyl group,    -   when n=1, if R2 is an aryl different from a naphthyl, or an        hetero aryl, substituted by one linear or branched, saturated or        not, C1-C7 alkyl, said aryl or heteroaryl is also substituted by        at least another group different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-h2):

wherein

-   -   Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,        -   provided that    -   if R2 is an aryl different from a naphthyl, or an hetero aryl,        substituted by one linear or branched, saturated or not, C1-C7        alkyl, said aryl or heteroaryl is also substituted by at least        another group, which is different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-h3):

wherein

-   -   Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is an aryl group, preferably a phenyl or a naphthyl group,        possibly mono or or polysubstituted, in particular        disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,    -   provided that    -   if R2 is an aryl different from a naphthyl, or an hetero aryl,        substituted by one linear or branched, saturated or not, C1-C7        alkyl, said aryl or heteroaryl is also substituted by at least        another group, which is different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n1):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n2):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n3):

wherein

-   -   Z represents O or S,    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds belonging to the group consisting of:

According to another embodiment, the present invention relates to theabove mentioned compounds belonging to the group consisting of:

According to another embodiment, the present invention relates to theabove mentioned compounds belonging to the group consisting of:

The above mentioned compounds present an inhibitory activity against atleast one kallikrein, among KLK5, KLK7 and KLK14, or even a combinationof two or three of said kallikreins.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂—Cl or —CH₂OCOC₂H₅, and    -   R2 represents        -   a pyridyl substituted by a Cl, or        -   a phenyl substituted, or not, either by a group —OCH₃ or by            one or two halogens chosen among Cl, Br or I.

Compounds having the formula (II) and the above mentioned significationsfor R1 and R2 present an inhibitory activity against KLK7.

The coumarin derivatives of formula II are enzyme inhibitors, moleculesthat binds to enzymes and decreases their activity.

A test to show the inhibitory activity consists in incubating KLK7 and acoumarin derivative and then determining the activity of KLK7 bycomparison of the initial rates to those obtained in control experimentswithout coumarin derivative. The values of “IC50” (inhibitorconcentrations giving 50% inhibition) express the inhibitory activity.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents:        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   —CH₂—Cl,        -   —CH₂OCOC₂H₅, or        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   and

    -   R2 represents        -   a pyridyl substituted by a Cl, or        -   a phenyl substituted, or not, either by a group —OCH₃ or by            one or two halogens chosen among Cl, Br or I,            providing at least one of R9 and R10 represents —CO—R5 or            —SO₂—R11, preferably R9 being —CO—R5 and R10 being hydrogen            or R9 being —SO₂—R11 and R10 being hydrogen.

Compounds having the formula (II) and the above mentioned significationsfor R1 and R2 present an inhibitory activity against KLK7.

The coumarin derivatives of formula II are enzyme inhibitors, moleculesthat binds to enzymes and decreases their activity.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents:        -   an hydrogen,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   —CH₂—Cl,        -   —CH₂—Br,        -   —CH₂—F,        -   —CH₂OCOC₂H₅, or        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   and

    -   R2 represents        -   a pyridyl substituted by a Cl, or        -   a phenyl substituted, or not, either by a group —OCH₃ or by            one or two halogens chosen among Cl, Br, F or I, or        -   a naphthyl substituted, or not, either by a group —OCH₃ or            by one or two halogens chosen among Cl, Br, F or I,            providing that:

    -   at least one of R9 and R10 represents —CO—R5 or —SO₂—R11,        preferably R9 being —CO—R5 and R10 being hydrogen or R9 being        —SO₂—R11 and R10 being hydrogen,        -   if R1=H, R2 can only represent a naphthyl.

Compounds having the formula (II) and the above mentioned significationsfor R1 and R2 present an inhibitory activity against KLK7.

The coumarin derivatives of formula II are enzyme inhibitors, moleculesthat binds to enzymes and decreases their activity.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

Compounds above show an inhibitory activity against KLK7.

According to another embodiment, the present invention relates to theabove mentioned compounds belonging to the group consisting of:

Compounds above show an inhibitory activity against KLK7.

According to another embodiment, the present invention relates to theabove mentioned compounds belonging to the group consisting of:

Compounds above show an inhibitory activity against KLK7.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂—Cl, —CH₂OCOCH₃, —CH₃, —NH₂, and its salts        thereof, or H, and    -   R2 represents:        -   an isoquinolinyl, or        -   —CH₃, or        -   a pyridyl, or        -   a phenyl, substituted or not by a halogen,    -   provided that        -   if R1=H, R2 can only represent an isoquinolinyl, and        -   if R1=CH₃, R2 can only represent a CH₃.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK5.

A test to show the inhibitory activity consists in incubating KLK5 and acoumarin derivative and then determining the activity of KLK5 bycomparison of the initial rates to those obtained in control experimentswithout coumarin derivative. The values of “IC50” (inhibitorconcentrations giving 50% inhibition) express the inhibitory activity.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂—Cl, —CH₂OCOCH₃, —CH₃, —CH₂—NH₂, and its salts        thereof, or H, and    -   R2 represents:        -   an isoquinolinyl, or        -   —CH₃, or        -   a pyridyl, or        -   a phenyl, substituted or not by a halogen,    -   provided that        -   if R1=H, R2 can only represent an isoquinolinyl, and        -   if R1=CH₃, R2 can only represent a CH₃.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK5.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂—Cl, —CH₂—Br, —CH₂—F, —CH₂OCOCH₃, —CH₃,        —CH₂—NH₂, and its salts thereof, or H, and    -   R2 represents:        -   an isoquinolinyl, or        -   —CH₃, or        -   a pyridyl, or        -   a phenyl, substituted or not by a halogen,    -   provided that        -   if R1=H, R2 can only represent an isoquinolinyl, and        -   if R1=CH₃, R2 can only represent a CH₃.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK5.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

Compounds above show an inhibitory activity against KLK5.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

Compounds above show an inhibitory activity against KLK5.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃ or —CH₂Cl, and    -   R2 represents a pyridyl or a phenyl, said pyridyl or phenyl        being mono or bisubstituted by one or two groups chosen among a        halogen, an amide, an acid, a —CH₃ or a —NO₂.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK14.

A test to show the inhibitory activity consists in incubating KLK14 anda coumarin derivative and then determining the activity of KLK14 bycomparison of the initial rates to those obtained in controlexperiments, without coumarin derivative. The values of “IC50”(inhibitor concentrations giving 50% inhibition) express the inhibitoryactivity.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃ or —CH₂Cl, and    -   R2 represents a pyridyl or a phenyl, said pyridyl or phenyl        being mono or bisubstituted by one or two groups chosen among a        halogen, an amide, an acid, a —CH₃, a —NO₂ or a —CN.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (II):

wherein

-   -   R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃, —CH₂Cl, —CH₂—Br or        —CH₂—F, and    -   R2 represents a pyridyl or a phenyl, said pyridyl or phenyl        being mono or bisubstituted by one or two groups chosen among a        halogen, an amide, an acid, a —CH₃, a —NO₂ or a —CN, in        particular by one halogen.

Compounds having the formula (II) and the significations for R1 and R2noted above show an inhibitory activity against KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

Compounds above show an inhibitory activity against KLK14.

According to another embodiment, the present invention relates to theabove mentioned compound:

Compound above shows an inhibitory activity against KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

Compounds above show an inhibitory activity against KLK14.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (Ib):

-   -   wherein    -   Z represents O or S,    -   R1 represents —CH₂Cl or —NH₂ or its salt thereof, and    -   R2 represents a pyridyl or a phenyl, said pyridyl or phenyl        being substituted or not by one or two halogens, one amide or        one ester.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (Ib):

-   -   wherein    -   Z represents O or S,    -   R1 represents —CH₂Cl or —CH₂—NH₂ or its salt thereof, and    -   R2 represents a pyridyl or a phenyl, said pyridyl or phenyl        being substituted or not by one or two halogens, one amide or        one ester.

According to another embodiment, the present invention relates to theabove mentioned compounds chosen among the group consisting of:

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,        -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl or an hetero aryl substituted            by one linear or branched, saturated or not, C1-C7 alkyl,            said aryl or heteroaryl is also substituted by at least            another group different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            Netherton syndrome, psoriasis, atopic eczema and allergic            contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,        -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            naphthyl, or a phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl different from a naphthyl, or            an hetero aryl, substituted by one linear or branched,            saturated or not, C1-C7 alkyl, said aryl or heteroaryl is            also substituted by at least another group, which is            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            Netherton syndrome, psoriasis, atopic eczema and allergic            contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,        -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl or an hetero aryl substituted            by one linear or branched, saturated or not, C1-C7 alkyl,            said aryl or heteroaryl is also substituted by at least            another group different from a C1-C7 alkyl,

    -   for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14,        aforesaid pathologies being Netherton syndrome.

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,        -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,        -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            naphthyl, or a phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl different from a naphthyl, or            an hetero aryl, substituted by one linear or branched,            saturated or not, C1-C7 alkyl, said aryl or heteroaryl is            also substituted by at least another group, which is            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies being Netherton syndrome.

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl or an hetero aryl substituted            by one linear or branched, saturated or not, C1-C7 alkyl,            said aryl or heteroaryl is also substituted by at least            another group different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that

    -   when n=0, then R1 can only represent a linear or branched,        saturated or not, C1-C7 alkyl, preferably a methyl group,        possibly substituted by an halogen, such that        -   if R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a            methyl group or a cycloalkyl group, preferably a cyclohexyl            group,

    -   when n=1,        -   if R1=H, then R2 can only represent an isoquinolinyl or a            naphthyl, or a phenyl substituted by two halogens, and        -   if R1≠H, then if R2 is an aryl different from a naphthyl, or            an hetero aryl, substituted by one linear or branched,            saturated or not, C1-C7 alkyl, said aryl or heteroaryl is            also substituted by at least another group, which is            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1b) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,        -   if R1 represents a group

-   -   -    wherein R9 and R10 are independently chosen among hydrogen            and a linear or branched, saturated or not, C1-C5 alkyl, or            a salt thereof, R2 is different from a pyridyl, and            represents in particular a phenyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1b) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl,        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,

    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,

    -   provided that:        -   if R2 is an aryl different from a naphthyl, or an hetero            aryl, substituted by one a linear or branched, saturated or            not, C1-C7 alkyl, said aryl or heteroaryl is also            substituted by at least another group different from a C1-C7            alkyl,        -   if R1 represents a group

-   -   -    wherein R9 and R10 are independently chosen among hydrogen            and a linear or branched, saturated or not, C1-C5 alkyl, or            a salt thereof, R2 is different from a pyridyl, and            represents in particular a phenyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (Ib) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents a group

-   -    or a salt thereof, wherein R9 and R10, independently from each        other, are chosen among:        -   hydrogen,        -   a linear or branched, saturated or not, C1-C5 alkyl,    -   and    -   R2 is a phenyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,    -   provided that:        -   if R2 is substituted by one a linear or branched, saturated            or not, C1-C7 alkyl, R2 is substituted by at least another            group different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (Ib) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents a group

-   -    or a salt thereof, wherein R9 and R10, independently from each        other, are chosen among:        -   hydrogen,        -   a linear or branched, saturated or not, C1-C5 alkyl,        -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and a            linear or branched, saturated or not, C1-C7 alkyl,            substituted or not by at least one halogen chosen among Cl,            F, I and Br,    -   at least one of R9 and R10 representing —CO—R5,    -   and    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (Ib) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents a group

-   -    or a salt thereof, wherein R9 and R10, independently from each        other, are chosen among:        -   hydrogen,        -   a linear or branched, saturated or not, C1-C5 alkyl,        -   —SO₂—R11, wherein R11 is a linear or branched, saturated or            not, C1-C7 alkyl,    -   at least one of R9 and R10 representing —SO₂—R11,    -   and    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (Ib) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents a linear or branched, saturated or not, C1-C7        alkyl, preferably a methyl group, substituted by a hydroxyl or a        —O—R12 group, wherein R12 is a linear or branched, saturated or        not, C1-C7 alkyl, preferably a hydroxyl, and    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (Ib) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents an amine

-   -    or a salt thereof, wherein R3 and R4, independently from each        other, are chosen among hydrogen and a linear or branched,        saturated or not, C1-C5 alkyl,    -   and    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates tocompounds of formula (I-1b) as presented below:

wherein

-   -   Z represents O or S,    -   R1 represents a group —O—R13, wherein R13 is chosen among        hydrogen and a linear or branched, saturated or not, C1-C7        alkyl, R13 being preferably a hydrogen,    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl group, possibly mono or            polysubstituted, in particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that:        -   if R2 is an aryl or an hetero aryl substituted by one a            linear or branched, saturated or not, C1-C7 alkyl, said aryl            or heteroaryl is also substituted by at least another group            different from a C1-C7 alkyl,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            psoriasis, atopic eczema and allergic contact dermatitis.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n1):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R′1 represents a group chosen among hydrogen and —O—R14, wherein        R14 is chosen among hydrogen and a linear or branched, saturated        or not, C1-C7 alkyl, R14 being preferably a hydrogen, R′1 being        preferably a hydrogen,

    -   provided that R′1 represents hydrogen when R1 does not represent        a —O—R13 group,

    -   and

    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            Netherton syndrome, psoriasis, atopic eczema and allergic            contact dermatitis, aforesaid pathologies being in            particular Netherton syndrome.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n2):

wherein

-   -   Z represents O or S,    -   R1 represents at least one group chosen among the group        consisting of:        -   hydrogen        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted, or not, by a halogen            chosen among Cl, F, I and Br,        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a methyl group, substituted by a hydroxyl or a            —O—R12 group, wherein R12 is a linear or branched, saturated            or not, C1-C7 alkyl, preferably a hydroxyl,        -   a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen            atom, and a linear or branched, saturated or not, C1-C7            alkyl, substituted or not by at least one halogen chosen            among Cl, F, I and Br,        -   a group —O—R13, wherein R13 is chosen among hydrogen and a            linear or branched, saturated or not, C1-C7 alkyl, R13 being            preferably a hydrogen,        -   an amine

-   -   -    or a salt thereof, wherein R3 and R4, independently from            each other, are chosen among hydrogen and a linear or            branched, saturated or not, C1-C5 alkyl, and        -   a group

-   -   -    or a salt thereof, wherein R9 and R10, independently from            each other, are chosen among:            -   hydrogen,            -   a linear or branched, saturated or not, C1-C5 alkyl,            -   —CO—R5, wherein R5 is chosen among a hydrogen atom, and                a linear or branched, saturated or not, C1-C7 alkyl,                substituted or not by at least one halogen chosen among                Cl, F, I and Br,            -   —SO₂—R11, wherein R11 is a linear or branched, saturated                or not, C1-C7 alkyl,

    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            Netherton syndrome, psoriasis, atopic eczema and allergic            contact dermatitis, aforesaid pathologies being in            particular Netherton syndrome.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-n3):

wherein

-   -   Z represents O or S,    -   R2 is a naphthyl group, in particular a 1-naphthyl or a        2-naphthyl group, possibly mono or polysubstituted, in        particular disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,            for its use for the treatment of pathologies involving an            excess of activity of at least one member of the kallikrein            family, preferably belonging to the group consisting of            KLK5, KLK7 and KLK14,            aforesaid pathologies belonging to the group consisting of            Netherton syndrome, psoriasis, atopic eczema and allergic            contact dermatitis, aforesaid pathologies being in            particular Netherton syndrome.

According to another embodiment, the present invention relates tocompounds of formula (I-h1) as presented below:

-   -   wherein n equals 0 or 1,        and wherein    -   if n=1, Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that    -   when n=0, R2 is a methyl group or a cycloalkyl group, preferably        a cyclohexyl group,    -   when n=1, if R2 is an aryl different from a naphthyl, or an        hetero aryl, substituted by one linear or branched, saturated or        not, C1-C7 alkyl, said aryl or heteroaryl is also substituted by        at least another group different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14,        aforesaid pathologies belonging to the group consisting of        Netherton syndrome, psoriasis, atopic eczema and allergic        contact dermatitis, aforesaid pathologies being in particular        Netherton syndrome.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-h2):

wherein

-   -   Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is chosen among the group consisting of:        -   a linear or branched, saturated or not, C1-C7 alkyl,            preferably a C1-C3 alkyl,        -   a C3-C6 cycloalkyl, preferably a C4-C6 cycloalkyl, more            preferably a cyclohexyl,        -   an aryl group, preferably a phenyl or a naphthyl group,            possibly mono or or polysubstituted, in particular            disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a group —NO₂,            -   a group —CN,            -   a combination of the above,    -   and        -   an heteroaryl group, preferably a pyridyl or an            isoquinolinyl, possibly mono or polysubstituted, in            particular disubstituted, by            -   a halogen chosen among Cl, F, I and Br, or            -   a linear or branched, saturated or not, C1-C7 alkyl, or            -   a group —CO—R6, R6 being chosen among the group                consisting of: —OH, —NH₂, or salt thereof, and —O—R7, R7                being a linear or branched, saturated or not, C1-C7                alkyl, or            -   a group —O—R8, R8 being a linear or branched, saturated                or not, C1-C7 alkyl, or            -   a combination of the above,    -   provided that    -   if R2 is an aryl different from a naphthyl, or an hetero aryl,        substituted by one linear or branched, saturated or not, C1-C7        alkyl, said aryl or heteroaryl is also substituted by at least        another group different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14,        aforesaid pathologies belonging to the group consisting of        Netherton syndrome, psoriasis, atopic eczema and allergic        contact dermatitis, aforesaid pathologies being in particular        Netherton syndrome.

According to another embodiment, the present invention relates to theabove mentioned compounds having the following formula (I-h3):

wherein

-   -   Z represents O or S,    -   R1 represents —CH₂—Br or —CH₂—F,    -   R2 is an aryl group, preferably a phenyl or a naphthyl group,        possibly mono or or polysubstituted, in particular        disubstituted, by        -   a halogen chosen among Cl, F, I and Br, or        -   a linear or branched, saturated or not, C1-C7 alkyl, or        -   a group —CO—R6, R6 being chosen among the group consisting            of: —OH, —NH₂, or salt thereof, and —O—R7, R7 being a linear            or branched, saturated or not, C1-C7 alkyl, or        -   a group —O—R8, R8 being a linear or branched, saturated or            not, C1-C7 alkyl, or        -   a group —NO₂,        -   a group —CN,        -   a combination of the above,    -   provided that    -   if R2 is an aryl different from a naphthyl, or an hetero aryl,        substituted by one linear or branched, saturated or not, C1-C7        alkyl, said aryl or heteroaryl is also substituted by at least        another group different from a C1-C7 alkyl,        for its use for the treatment of pathologies involving an excess        of activity of at least one member of the kallikrein family,        preferably belonging to the group consisting of KLK5, KLK7 and        KLK14,        aforesaid pathologies belonging to the group consisting of        Netherton syndrome, psoriasis, atopic eczema and allergic        contact dermatitis, aforesaid pathologies being in particular        Netherton syndrome.

According to another embodiment, the present invention relates to thecompound of formula (II11)

According to another embodiment, the present invention relates to acompound selected from the group comprising:

According to another embodiment, the present invention relates to acompound selected from the group comprising:

The synthesis of the coumarin derivatives of the invention is describedin the patent of Reboud-Ravaux et al (WO9855472) and in the literature(Pochet L., Doucet C., Schynts M., Thierry N., Boggetto N., Pirotte B.,Jiang K. I., Masereel B., de Tullio P., Delarge J., Reboud-Ravaux M., J.Med. Chem, 1996, 39, 2579-2585; Doucet C., Pochet L., Thierry N.,Pirotte B., Delarge J., Reboud-Ravaux M., J. Med. Chem, 1999, 42,4161-4171). On the other hand, the compound CFL33 is a new coumarinderivative. Its synthesis is described in the example 1.

Compounds SMB28 and SMB33 are new coumarin derivatives. Their synthesisis respectively described in examples 1.2 and 1.3.

Compounds JFR5, JFR7, JFR8, JFR9 and JFR11 are new coumarin derivatives.Their synthesis is described in examples 1.6 to 1.10.

According to another embodiment, the present invention relates to thecompound of formula CFL33 for its use as drug.

According to another embodiment, the present invention relates to acompound selected from the group comprising SMB28 and SMB33, for its useas drug.

According to another embodiment, the present invention relates to acompound selected from the group comprising JFR5, JFR7, JFR8, JFR9 andJFR11, for its use as drug.

According to another embodiment, the present invention is thereforedirected towards the preparation of a pharmaceutical compositioncomprising as active substance a compound of formula CFL33 inassociation with a pharmaceutically acceptable carrier.

According to another embodiment, the present invention is thereforedirected towards the preparation of a pharmaceutical compositioncomprising as active substance a compound selected from the groupcomprising SMB28 and SMB33 in association with a pharmaceuticallyacceptable carrier.

According to another embodiment, the present invention is thereforedirected towards the preparation of a pharmaceutical compositioncomprising as active substance a compound selected from the groupcomprising JFR5, JFR7, JFR8, JFR9 and JFR11 in association with apharmaceutically acceptable carrier.

The invention is therefore directed towards the preparation of apharmaceutical composition containing a compound of formula CFL33 as adrug in which said compound has a kallikrein-inhibitory activity. Thiscomposition is characterized in that it comprises, in a pharmaceuticallyacceptable carrier that is compatible with the method of administrationselected for said composition, a compound of formula CFL33.

The invention is therefore directed towards the preparation of apharmaceutical composition containing a compound selected from the groupcomprising SMB28 and SMB33 as a drug in which said compound has akallikrein-inhibitory activity. This composition is characterized inthat it comprises, in a pharmaceutically acceptable carrier that iscompatible with the method of administration selected for saidcomposition, aforesaid compound selected from the group comprising SMB28and SMB33.

The invention is therefore directed towards the preparation of apharmaceutical composition containing a compound selected from the groupcomprising JFR5, JFR7, JFR8, JFR9 and JFR11 as a drug in which saidcompound has a kallikrein-inhibitory activity. This composition ischaracterized in that it comprises, in a pharmaceutically acceptablecarrier that is compatible with the method of administration selectedfor said composition, aforesaid compound selected from the groupcomprising JFR5, JFR7, JFR8, JFR9 and JFR11.

The term “pharmaceutically acceptable carrier” is intended to mean amedium that is compatible with the skin, the mucous membranes andsystemic administration.

The composition according to the invention can be administeredtopically. Preferably, the pharmaceutical composition is packaged in aform suitable for topical application.

When used topically, the pharmaceutical composition according to theinvention is more particularly for use in the treatment of the skin andthe mucous membranes and may be in liquid, pasty or solid form, and moreparticularly in the form of ointments, creams, solutions or gels.

The compositions used for topical application have a concentration ofcompound according to the invention of generally between 0.001% and 20%by weight, relative to the total weight of the composition.

The composition according to the invention can be administeredsystemically. Preferably, the pharmaceutical composition is packaged ina form suitable for systemic administration. The routes ofadministration can be parenteral, digestive, rectal, transcutaneous.

More particularly, the composition according to the invention may be inthe form of injectable solutions or suspensions, tablets, capsules,powders or preparation for trans dermal use.

The posology may vary according to the severity of the disease, thepatient's age and weight and the route of administration. Generally, theunit dose may be of 1 to 200 mg per taking and the daily dose may be of2 to 500 mg.

The pharmaceutical composition as described above may also contain inertadditives or pharmacodynamically active additives as regards thepharmaceutical compositions, or combinations of theses additives.

According to another embodiment, the present invention relates to acomposition comprising a compound of formula CFL33 for its use for thetreatment of skin pathologies. According to another embodiment, thepresent invention relates to a composition comprising a compoundselected from the group comprising SMB28 and SMB33 for its use for thetreatment of skin pathologies.

According to another embodiment, the present invention relates to acomposition comprising a compound selected from the group comprisingJFR5, JFR7, JFR8, JFR9 and JFR11 for its use for the treatment of skinpathologies.

According to another embodiment, the present invention relates to acomposition comprising a compound of formula CFL33 wherein said skinpathologies belong to the group consisting of Netherton syndrome, atopicdermatitis, psoriasis, eczema and peeling skin syndrome, preferablyNetherton syndrome.

According to another embodiment, the present invention relates to acomposition comprising a compound of formula CFL33 wherein said skinpathologies belong to the group consisting of Netherton syndrome,psoriasis, atopic eczema and allergic contact dermatitis, preferablyNetherton syndrome.

According to another embodiment, the present invention relates to acomposition comprising a compound selected from the group comprisingSMB28 and SMB33 wherein said skin pathologies belong to the groupconsisting of Netherton syndrome, atopic dermatitis, psoriasis, eczemaand peeling skin syndrome, preferably Netherton syndrome.

According to another embodiment, the present invention relates to acomposition comprising a compound selected from the group comprisingSMB28 and SMB33 wherein said skin pathologies belong to the groupconsisting of Netherton syndrome, psoriasis, atopic eczema and allergiccontact dermatitis, preferably Netherton syndrome.

According to another embodiment, the present invention relates to acomposition comprising a compound selected from the group comprisingJFR5, JFR7, JFR8, JFR9 and JFR11 wherein said skin pathologies belong tothe group consisting of Netherton syndrome, atopic dermatitis,psoriasis, eczema and peeling skin syndrome, preferably Nethertonsyndrome.

According to another embodiment, the present invention relates to acomposition comprising a compound selected from the group comprisingJFR5, JFR7, JFR8, JFR9 and JFR11 wherein said skin pathologies belong tothe group consisting of Netherton syndrome, psoriasis, atopic eczema andallergic contact dermatitis, preferably Netherton syndrome.

The compound CFL33 according to the invention is suitable for userelated to the treatment or prevention of skin disorders such asNetherton syndrome, atopic dermatitis, psoriasis, eczema and peelingskin syndrome, preferably Netherton syndrome.

The compound CFL33 according to the invention is suitable for userelated to the treatment or prevention of skin disorders such asNetherton syndrome, psoriasis, atopic eczema and allergic contactdermatitis, preferably Netherton syndrome.

The compound selected from the group comprising SMB28 and SMB33according to the invention is suitable for use related to the treatmentor prevention of skin disorders such as Netherton syndrome, atopicdermatitis, psoriasis, eczema and peeling skin syndrome, preferablyNetherton syndrome.

The compound selected from the group comprising SMB28 and SMB33according to the invention is suitable for use related to the treatmentor prevention of skin disorders such as Netherton syndrome, psoriasis,atopic eczema and allergic contact dermatitis, preferably Nethertonsyndrome.

The compound selected from the group comprising JFR5, JFR7, JFR8, JFR9and JFR11 according to the invention is suitable for use related to thetreatment or prevention of skin disorders such as Netherton syndrome,atopic dermatitis, psoriasis, eczema and peeling skin syndrome,preferably Netherton syndrome.

The compound selected from the group comprising JFR5, JFR7, JFR8, JFR9and JFR11 according to the invention is suitable for use related to thetreatment or prevention of skin disorders such as Netherton syndrome,psoriasis, atopic eczema and allergic contact dermatitis, preferablyNetherton syndrome.

FIG. 1: This figure presents the activation cascade involvingkallikreins. In Netherton syndrome LEKTI loses its faculty toefficiently control the KLK5, leading to an abnormal skin desquamationdue to an increase of the degradation of the corneodesmosomes proteins.Synthetic inhibitors are susceptible to control the double KLK5function, that is direct degradation and other proteases activation,KLK7 and KLK14, this one activating pro-elastase.

FIG. 2 and FIG. 3 present cell viability of normal human keratinocytesafter treatment with some compounds of the present invention,respectively at 1 μM (FIG. 2) and 10 μM (FIG. 3).

FIG. 4 shows the mean+/−SD of the expression of the target genesrelative to the expression of the housekeeping gene: (A) TSLP, (B) IL-8,(C) TNFα, (D) MDC and (E) TARC.

FIG. 5 presents the evaluation of the cytotoxic effect of coumarincompounds JFR5, JFR8, JFR9 and JFR11 on healthy human keratinocytes at 1(hatched) and 10 (cross hatched) μM after a 48 h treatment and neutralred staining. Three independent experiments were performed for eachcompound.

FIG. 6 illustrates the effect of JFR9 compound (5 μM) efficacy on thetotal protease activity of transgenic KLK5 mice skin section, by in situzymography.

The protease activity is shown with a gradient of fluorescence. Thefluorescence intensity represents the cleavage efficiency of a caseinsubstrate coupled to a FITC group.

Control (+): no inhibitor added; control (−): addition of a coumarincompound that does not inhibit proteases.

EXAMPLES Example 1 Synthesis of CFL33, isoquinolin-1-yl2-oxo-2H-1-benzopyran-3-carboxylate

1.0 g of the commercially available 2-oxo-2H-1-benzopyran-3-carboxylicacid and 10 ml of thionyl chloride were refluxed for 3 h. The resultingsolution was evaporated under reduced pressure. The residue wassuspended in 10 ml anhydrous toluene. The solvent was eliminated bydistillation under reduced pressure. The two last steps were repeatedtwice. The residue was dispersed in 10 ml dioxane. To this suspensionwere added 1-hydroxyquinoleine (1.1 éq.) and anhydrous pyridine (1.1eq.). After 90 min stirring at room temperature, the solvent was removedby distillation under reduced pressure. The residue was solubilized inchloroform and the organic phase was washed three times with HCl 0.1N,then dried over MgSO₄. The solvent was evaporated under reduced pressureand the residue obtained was recrystallized in ethyl acetate.

-   -   white solid; m.p. 197-200° C.

¹H NMR (500 MHz) DMSO-d₆: 6.87 (d, 1H, 4-H isoquin.), 7.47 (t, 1H, 6-Hcoumar.), 7.52 (d, 1H, 8-H coumar.), 7.58 (t, 1H, 7-H isoquin.), 7.75(m, 2H, 7-H coumar.+5-H isoquin.), 7.84 (m, 2H, 6-H+3-H isoquin.), 7.93(d, 1H, 5-H coumar.), 8.16 (d, 1H, 8-H isoquin.), 8.56 (s, 1H, 4-Hcoumar.).

Example 1.2 Synthesis of SMB28, 2-iodophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate

To the suspension of the acid chloride of6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol)obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489)in anhydrous dioxane (10 mL) was added 2-iodophenol (5 mmol) andpyridine (0.4 mL). After 12 h stirring at room temperature, the solventwas evaporated under vacuum and the residue was suspended in methanol.The resulting precipitate was collected by filtration, washed withmethanol and dried. The solid was crystallized in ethyl acetate (45%);mp: 156-158° C.

Example 1.3 Synthesis of SMB33, 2-cyanophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate

To the suspension of the acid chloride of6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol)obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489)in anhydrous dioxane (10 mL) was added 2-cyanophenol (5 mmol) andpyridine (0.4 mL). After 12 h stirring at room temperature, the solventwas evaporated under vacuum and the residue was suspended in methanol.The resulting precipitate was collected by filtration, washed withmethanol and dried. The solid was crystallized in ethyl acetate (40%);mp: 181-183° C.

General synthetic pathway to naphthyl2-oxo-2H-1-benzopyran-3-carboxylates

Synthesis of dinaphthyl esters of malonic acid

The mixture of malonic acid (2 g, 19.2 mmol), the appropriate naphthol(2 eq., 38.4 mmol) and phosphoryl chloride (2 eq., 38.4 mmol) was heatedat 100° C. for 90 minutes. The reaction mixture was then carefullypoured on a cooled 1% w/v aqueous solution of sodium hydroxide (50 mL).The resulting precipitate of the title compound was collected byfiltration, washed with water, dried and recrystallized in methanol(yields: 25-30%). The white solid of the title compound was used in thenext step without further purification.

Synthesis of naphthyl 2-oxo-2H-1-benzopyran-3-carboxylates

The solution of salicylaldehyde (0.4 g, 3.28 mmol) and the appropriatedinaphthyl malonate (1.5 eq., 4.92 mmol) in dioxane (12 mL) wassupplemented with 8 drops of piperidine and 4 drops of glacial aceticacid and stirred for 30 minutes at room temperature. At the end of thereaction, the solvent was removed by distillation under reduced pressureand the residue was triturated with cold methanol (20 mL). The resultingprecipitate was collected by filtration, washed with cold methanol anddried. The white solid of the title compound was recrystallized in amixture of methylene chloride and hexane (yields: 75-80%).

Example 1.4 1-Naphthyl 2-oxo-2H-1-benzopyran-3-carboxylate (JFR1)

1-Naphthyl 2-oxo-2H-1-benzopyran-3-carboxylate (JFR1) was obtainedaccording to the above-mentioned general procedure, starting from1-naphthol.

m.p.: 159-160° C.

Example 1.5 2-Naphthyl 2-oxo-2H-1-benzopyran-3-carboxylate (JFR2)

2-Naphthyl 2-oxo-2H-1-benzopyran-3-carboxylate (JFR2) was obtainedaccording to the above-mentioned general procedure, starting from2-naphthol.

m.p.: 166-167° C.

General synthetic pathway to halophenyl6-halomethyl-2-oxo-2H-1-benzopyran-3-carboxylates

Synthesis of di(halo)phenyl esters of malonic acid

The mixture of malonic acid (2 g, 19.2 mmol), the appropriate halophenol(2 eq., 38.4 mmol) and phosphoryl chloride (2 eq., 38.4 mmol) was heatedat 100° C. for 90 minutes. The reaction mixture was then carefullypoured on a cooled 1% w/v aqueous solution of sodium hydroxide (50 mL).The resulting precipitate of the title compound was collected byfiltration, washed with water, dried and recrystallized in methanol(yields: 65-80%). The white solid of the title compound was used in thenext step without further purification.

Synthesis of (halo)phenyl6-hydroxymethyl-2-oxo-2H-1-benzopyran-3-carboxylates

The solution of 5-hydroxymethylsalicylaldehyde (Stoermer et al. Ber.1901, 34, 2455-2460) (0.4 g, 2.62 mmol) and the appropriatedi(halo)phenyl malonate (1.5 eq., 3.94 mmol) in dioxane (12 mL) wassupplemented with 8 drops of piperidine and 4 drops of glacial aceticacid and stirred for 30 minutes at room temperature. At the end of thereaction, the solvent was removed by distillation under reduced pressureand the residue was triturated with cold methanol (10-20 mL). Theresulting precipitate was collected by filtration, washed with coldmethanol and dried (yields: 70-85%). The white solid of the titlecompound was used in the next step without further purification.

Synthesis of (halo)phenyl6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylates

The appropriate (halo)phenyl6-hydroxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (0.4 g, ˜0.7 mmol)was dissolved in methylene chloride (10 mL) and then supplemented withpyridine (1.0 eq.) and thionyl bromide (1.15 eq.). The reaction mixturewas heated under reflux for 90 minutes. After cooling, the reactionmedium was poured onto water (20 mL). The organic layer was collected,dried over magnesium sulfate, filtered and concentrated under reducedpressure. The residue of the title compound was recrystallized in amixture of methylene chloride and hexane (yields: 15-50%).

Example 1.6 Phenyl 6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate(JFR5)

Phenyl 6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR5) wasobtained according to the above-mentioned general procedure, startingfrom phenol.

m.p.: 186-187° C.

Example 1.7 3-Fluorophenyl6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR11)

3-Fluorophenyl 6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR11)was obtained according to the above-mentioned general procedure,starting from 3-fluorophenol.

m.p.: 189-190° C.

Example 1.8 3-Chlorophenyl6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR9)

3-Chlorophenyl 6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR9)was obtained according to the above-mentioned general procedure,starting from 3-chlorophenol.

m.p.: 186-187° C.

Example 1.9 3-Bromophenyl6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR8)

3-Bromophenyl 6-bromomethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR8)was obtained according to the above-mentioned general procedure,starting from 3-bromophenol.

m.p.: 185-186° C.

Synthesis of (halo)phenyl6-fluoromethyl-2-oxo-2H-1-benzopyran-3-carboxylates

The appropriate (halo)phenyl6-hydroxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (0.4 g, ˜0.7 mmol)was dissolved in methylene chloride (10 mL) and the resulting solutioncooled on an ice bath was supplemented with Ishikawa's reagent (2.5eq.). The reaction mixture was stirred for 30 minutes at 0° C. and thenheated under reflux for 90 minutes. After cooling, the reaction mediumwas poured onto water (20 mL). The organic layer was collected, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue of the title compound was purified by columnchromatography on silicagel (eluent: methylene chloride) and thenrecrystallized in a mixture of methylene chloride and hexane (yields:15-55%).

Example 1.10 4-Chlorophenyl6-fluoromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR7)

4-Chlorophenyl 6-fluoromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (JFR7)was obtained according to the above-mentioned general procedure,starting from 4-chlorophenol.

m.p.: 216-218° C.

Example 2 Biological results, enzyme and inhibition assays

In the examples described below:

-   -   DMSO means “dimethylsulfoxide”    -   Tris-HCl means “tris(hydroxymethyl)aminomethane, hydrogen        chloride>>    -   Tween 20 refers to polysorbate 20 or polyoxyethylene (20)        sorbitan monolaurate    -   The Hill number provides a way to characterize the binding of a        ligand to a macromolecule.

Kallikreins KLK5, KLK7 and KLK14 activities were determined bymonitoring the hydrolysis of the appropriate fluorogenic substrate(λ_(exc)=355, =460 nm) for 15 min at 37° C. in the presence of theuntreated kallikrein (control) or kallikrein that had been incubatedwith a test compound. Substrate and compounds were previously dissolvedin DMSO, with the final solvent concentration kept constant at 2% (v/v)(KLK 5 and 14), and 4% (v/v) (KLK7). The composition of the activitybuffers (pH 8.0) was 100 mM Tris-HCl, 150 mM NaCl, 0.01% (v/v) Tween 20for the KLK5 assay, and 100 mM Tris-HCl, 1M NaCl, 0.01% (v/v) Tween 20in the KLK 7 and 14 assays. The final concentrations were 0.6 nM (KLK5)and 100 μM (Boc-Val-Pro-Arg-AMC) (KLK5 assay), 8 nM (KLK7) and 40 μM(Suc-Leu-Leu-Val-Tyr-AMC, AMC:7-amino-4-methyl-coumarin) (KLK7 assay),and 0.17 nM (KLK14) and 10 μM (Boc-Val-Pro-Arg-AMC) (KLK14 assay). Usingthe appropriate substrate, the coumarinic compounds (0.01-100 μM) weretested in duplicate for each inhibitor concentration to detect theirinhibitory potential. The enzyme and the inhibitors were incubated for15 min before the determination of the enzyme activity. Initial ratesdetermined in control experiments (V₀) were considered to be 100% of thepeptidase activity; initial rates below 100% were considered to beinhibitions. The inhibitory activity of compounds was expressed as IC₅₀(inhibitor concentrations giving 50% inhibition). The values of IC₅₀were calculated by fitting the experimental data to the equation:

%Inhibition=100×(1−V _(i) /V ₀)=100[I] ₀/(IC ₅₀ +[I] ₀),

or equation:

%Inhibition=100[I] ₀ ^(nH)/(IC ₅₀ ^(nH) +[I] ₀ ^(nH)), n _(H) is theHill number.

Example 3 Characterization of the inhibition reversibility

To examine the putative covalent nature of the inhibition by coumarins,percentage of inhibition was monitored as function of time; a putativeenzyme reactivation by hydroxylamine was detected. The reaction mixturescontaining the inhibited enzyme were treated with 0.5 M hydroxylamine atpH 7.5 and 37° C. during 30 min. Enzyme activity of aliquots wasmonitored and compared to a control. The fast reactivation in thepresence of hydroxylamine indicated the formation of a stableacyl-enzyme; the absence of reactivation was in agreement with a suicideinactivation.

The results obtained for the compounds of the invention are shown intables A and A2.

The tests were realized at 37° C. after 15 min of incubation at pH 8. Inthese tables, <<NI>> means non-inhibitor and ND non-determined

TABLE A IC₅₀ (μM) or % Inhibition molecule name KLK5 KLK7 KLK14

MFS7 26% (50 μM) 0.235 ± 0.009 45% (100 μM)

MFS36 50% (100 μM) 0.209 ± 0.006 100% (100 μM)

LP15 NI 1.9 ± 0.1 37% (100 μM)

IK11 37.4% (50 μM) 63% (100 μM) 43 ± 4

IK1 26.3 ± 1.4 2.7 ± 0.1 38 ± 5

IK3 NI NI 77% (100 μM)

LP60 112 ± 6 1.44 ± 0.02 46% (100 μM)

IK5 36.9 ± 4.2 5.8 ± 0.2 89 ± 10

LP73 NI 0.063 ± 0.004 NI

LP74 1.3 ± 0.2 0.195 ± 0.024 54 ± 6 μM

LP72 59 ± 9 0.495 ± 0.037 50% (100 μM)

LP51 26% (50 μM) 0.25 ± 0.01 30% (100 μM)

LP8 49% (100 μM) 0.103 ± 0.005 40% (100 μM)

LP53 34% (50 μM) 0.065 ± 0.003 41% (100 μM)

LP14 48% (100 μM) 0.077± 0.003 70% (100 μM)

IK4 21.6 ± 5 7.8 ± 0.6 30 ± 8

IK2 NI 0.68 ± 0.01 67% (100 μM)

LP46 31% (50 μM) ND 31 ± 6

LP55 NI 8.4 ± 0.2 NI

LP75 80 ± 8 0.136 ± 0.012 NI

LP61 NI 0.130 ± 0.005 NI

CFL16 40% (100 μM) 0.9 ± 0.4 73% (100 μM)

CFL5 35% (100 μM) 0.50 ± 0.04 39 ± 4

CFL21 [121 ± 5] 22% (100 μM) 43% (100 μM)

CFL25 44 ± 10 ND 68 ± 9

CFL15 47% (100 μM) 0.352 ± 0.055 45% (100 μM)

CFL7 NI 33% (100 μM) 33% (100 μM)

MFS35 NI 55% (100 μM) 71% (100 μM)

IK8 ≈40 64.3 ± 2.7 64% (100 μM)

IK10 23% (50 μM) NI NI

IK9 22% (50 μM) NI NI

CFL4 NI 5.01 ± 0.4 60% (50 μM)

CFL17 NI 33% (100 μM) 50% (50 μM)

LP7 NI 0.463 ± 0.007 NI

LP16 NI 47% (50 μM) NI

IK13 NI 34% (100 μM) 72% (100 μM)

LP71 182 ± 14 NI NI

LP18 78 ± 12 4.9 ± 0.3 30 ± 2

LP42 22% (50 μM) 52% (100 μM) NI

LP76 30% (50 μM) 25% (50 μM) 35% (50 μM)

LP2 NI 0.128 ± 0.030 NI

D5 90% (100 μM) 61% (100 μM) 38% (100 μM)

MFS2 54 ± 2 26.8 ± 1.5 73 ± 14

MFS3 39% (50 μM) 20.9 ± 0.9 48% (100 μM)

LP43 49% (100 μM) 30% (100 μM) 49% (100 μM)

D9 80% (100 μM) NI 40% (100 μM)

CFL33 7.0 ± 0.4 NI 61% (100 μM)

LP41 32% (100 μM) 0.39 ± 0.03 67% (100 μM)

IK48 27% (50 μM) 9.7 ± 1.3 32% (50 μM)

MH30 25% (50 μM) 33.2 ± 1.4 32% (50 μM)

SMB27 NI 42% (50 μM) 27% (50 μM)

SMB26 NI 52% (10 μM) NI

SMB28 NI 82.2 ± 13.2 NI

IK53 NI 54% (10 μM) NI

MH52 NI 58% (10 μM) NI

IK49 NI 54% (10 μM) NI

MH24 NI 33.2 ± 1.4 42% (50 μM)

MH8 NI 25% (50 μM) NI

MH14 NI 35% (50 μM) NI

SMB33 NI NI 27% (50 μM)

MH22 32% (50 μM) 100% (50 μM) 85% (50 μM)

TABLE A2 IC₅₀ (nM) or % d’inhibition Compound KLK5 KLK7 KLK14

ni 53% (50 μM) ni JFR1

ni 30% (50 μM) ni JFR2

34% (50 μM) 249 ± 3.5 53% (50 μM) JFR5

ni 30% (50 μM) ni JFR7

1470 ± 60 57 ± 2 3000 ± 100 JFR8

920 ± 70 63.7 ± 1.7 2900 ± 100 JFR9

42% (50 μM) 198 ± 8 48% (50 μM) JFR11

62% (100 μM) 5.7 ± 0.3 60% (100 μM) MFS33

Examples of coumarin derivatives presenting a selective activity againstKLK5, KLK7 and KLK14 are listed in Table B.

An acceptable threshold of inhibition corresponds for example to 30% at100 μM.

TABLE B Enzyme Molecule KLK5 LP71, CFL33, IK9, IK10, D9 KLK7 LP2, LP42,LP51, LP55, LP72, LP74, MFS7, CFL15, SMB26, SMB28, IK53, MH52, IK49,MH8, MH14, JFR1, JFR2, JFR7, LP14, LP8, IK2, MFS36, LP53, LP73, JFR9,JFR8 KLK14 MFS35, CFL21, CFL17, IK3, IK13, SMB33

Example 4 Cytotoxicity in human keratinocytes using the Neutral RedUptake (NRU) cytotoxicity test

The NRU cytotoxicity assay procedure is a cell survival/viabilitychemosensitivity assay based on the ability of viable cells toincorporate and bind neutral red (NR), a supravital dye. NR is a weakcationic dye that readily penetrates cell membranes by non-ionicdiffusion and accumulates intracellularly in lysosomes. Alterations ofthe cell surface or the sensitive lysosomal membrane lead to lysosomalfragility and other changes that gradually become irreversible. Suchchanges caused by the action of xenobiotics result in a decreased uptakeand binding of NR. It is thus possible to distinguish between viable,damaged, or dead cells, which is the basis of this assay. Aftertreatment with the small-molecules inhibitors, NR uptake in cells willbe measured by spectrophotometry at 540±10 nm

Day 0: Cell Preparation

Keratinocytes from healthy persons or patients with Netherton syndromeare seeded at the density of 4000 cells in 125 μL of medium per well in96-well plates.

The culture medium is made of:

-   -   half of complete Green medium: 60% (Dulbecco's Modified Eagle        Media), 30% Ham's F12, 10% FCS, 180 mM adenin, 5 μg/mL insulin,        0.4 μg/mL hydrocortisone, 10 nM cholera toxin, 2 nM        triiodothyronin, 10 ng/mL human recombinant EGF, 100 U/mL        penicillin G/streptomycin.    -   half of a basal medium (Epilife—Cascade Biologics) allowing        keratinocytes culture without feeders.

2—Day 2: Cell Treatment

After seeding, cells are incubated for 48 hours in the followingexperimental conditions: 37° C.±1° C., 90%±5.0% humidity, and 5%±1%CO₂/air. This incubation period allows for cell recovery and adherenceand progression to exponential growth phase.

Prepare inhibitors solutions 2-fold more concentrated than desired. Add125 μL of these solutions to the wells without changing or removing themedium (125 μL).

A control with the vehicle alone (DMSO) is made.

A minimum of 3 wells per each experimental condition is done.

3—Day 4: NRU Measurement

48 h hours after the beginning of the treatment, carefully remove themedium (containing the tested inhibitor) and rinse the cells verycarefully with 250 μL pre-warmed PBS.

Add 250 μL NR medium and incubate (37° C.±1° C., 90%±5% humidity, and5.0%±1% CO₂/air) for 3±0.1 h. NR medium is the culture medium containing33 μg/mL of NR. After incubation, remove the NR medium, and carefullyrinse cells with 250 μL pre-warmed PBS.

Decant and blot PBS from the plate.

Add exactly 100 μL NR Desorb (50% ETOH/1% acetic acid) solution to allwells, including blanks.

Shake microtiter plate rapidly on a microtiter plate shaker for 20-45min to extract NR from the cells and form a homogeneous solution. Platesshould be protected from light by using a cover during shaking.

Plates should be still for at least five minutes after removal from theplate shaker.

Measure the absorption (within 60 minutes after adding NR Desorbsolution) of the resulting colored solution at 540 nm±10 nm in amicrotiter plate reader (spectrophotometer), using the blank as areference.

4—Data Analysis

The experiments are performed three times on three different days foreach inhibitor.

A calculation of cell viability expressed as NRU is made for eachconcentration of the tested inhibitor by using the mean NRU of the threereplicate values per each concentration. This value is compared with themean NRU of all vehicle values. Relative cell viability is thenexpressed as percent of untreated vehicle control (DMSO).

Example 5 Cell viability

Normal human keratinocytes were seeded in a 96-well tissue cultureplate. At 20% of confluence, molecules were added in the culture mediumand incubated for 48 h. Neutral red medium was added to every well foran incubation period of 3 h, then the dye was extracted with acidifiedethanol solution. Data (FIGS. 2 and 3) represent the mean cell viabilityafter treatment+/−SD compared to mean viability of cells treated withthe vehicle only (DMSO). Data represent the mean of 5 individualexperiments.

No noticeable cytotoxicity on human normal keratinocytes was observed at1 and 10 μM when assayed using the neutral red uptake test for LP7,LP14, LP41, LP53, LP55, LP61, LP73, LP76, MFS7, MFS33, CFL5, CFL33, IK2and IK4.

No noticeable cytotoxicity on human normal keratmocytes was observed at1 and 10 mM when assayed using the neutral red uptake test for JFR5, 8,9 and 11 (FIG. 5).

Toxicity was observed for IK3 at 1 and 10 μM reaching 16.09±8.32% at 1μM and 47.1±4.43% at 10 μM.

Example 6 Inhibitory effect of compounds of the invention on theexpression of pro-allergic and inflammatory molecules in Nethertonsyndrome patient keratinocytes 1—Cell Preparation:

250,000 keratinocytes from a Netherton syndrome patient (NSK) wereseeded in 6 well plates in 2 mL of medium made of: (a) half of completeGreen medium: (Dulbecco's Modified Eagle Media) 60%; Ham's F12 30%; FCS10%; adenin 180 mM; insulin 5 μg/mL; hydrocortisone 0.4 μg/mL; choleratoxin 10 nM; triiodothyronin 2 nM; human recombinant EGF 10 ng/mL;penicillin G/streptomycin 100 U/mL; (b) half of a basal medium(Epilife—Cascade Biologics).

When confluent, cells were washed 5 times with PBS and 2 mL of completeGreen medium without FCS (fetal calf serum) were added per well.

2—Treatment of Cells with Inhibitors:

Inhibitors were added in the culture medium 24 h after medium renewal.

3—Arrest of the Cell Culture and RNA Extraction 72 h after Beginning ofthe Treatment

The supernatant was removed and cells were washed once with PBS.

350 μL of RLT lysis buffer (Mini Kit QIAGEN)+β-mercapto-ethanol (0.1%)were added per well to extract total RNA. The cell lysate was kept at−80° C. before RNA extraction (Mini Kit QIAGEN).

4—Measurement of KLK5 Activity Inhibition

In this in cellulo test, KLK5 activity was evaluated by an indirectmethod. Indeed KLK5 induces TSLP (thymic stromal lymphopoietin), TNFα(tumor necrosis factor alpha) and IL-8 (interleukin 8) expression. IfKLK5 activity is inhibited, the expression of these cytokines will bereduced.

The relative amount of TSLP, TNFα and IL-8 transcripts [relative to HPRT(hypoxanthine phosphoribosyltransferase 1) housekeeping gene] wascompared between cells treated or not treated with the inhibitors. Theratio <<treated/not treated>> relative to housekeeping gene reflectsKLK5 inhibition.

Two other genes showed increased expression in NSK i.e. MDC (macrophagederived cytokine or CCL22) and TARC (thymus and activation regulatedchemokine or CCL17). Their expression had also been studied even iftheir mechanism of induction is not known yet.

5—Results

The effect of LP73 and CFL33 on the expression of the describedpro-allergic and inflammatory cytokines was analyzed on keratinocytesfrom two different NS patients. Each experiment was performed twice(FIG. 4).

LP73 at the dose of 1 μM significantly inhibited the expression of TSLP(p=0.0088), IL-8 (p=0.0269), TNFα (p=0.0004), MDC (p<0.0001) and TARC(p=0.0004) whereas at the dose of 10 μM, it only inhibited theexpression of TSLP (p=0.002) and TARC (p=0.0461).

CFL33 at the dose of 1 μM significantly inhibited the expression of IL-8(p=0.0309), MDC (p<0.0001) and TARC (p=0.0078) only.

Example 6bis Study on a mouse model of Netherton syndrome

JFR9 efficacy has been assayed on transgenic KLK5 mice skin section byin situ zymography (FIG. 6). These mice overexpress KLK5 and reproducethe phenotypic characteristics of Netherton syndrome. It has been shownthat JFR9 molecule (5 μM) decreased significantly the total proteaseactivity of the transgenic KLK5 mice skin section.

Example 7 Evaluation of the efficacy of coumarin derivatives of theinvention on psoriasis, atopic eczema and allergic contact dermatitisskin pathologies

To analyze whether coumarin derivatives have an efficacy on psoriasis,atopic eczema and allergic contact dermatitis skin pathologies, in situzymographies on skin sections can be performed. The total proteaseactivity can be visualized, as well as specific KLK5 and KLK7 activitiesdirectly in the tissue.

In situ zymography allows the study of protease activity in tissue. Skinsections of lesional skin are incubated in the presence, or not, of thetested compound and incubated 0/N with a specific substrate coupled to afluorochrome (casein can be used as substrate to assess total proteaseactivity or KLK5 and KLK7 specific substrates can be used to evaluateKLK5 and KLK7 activities. When the substrate is cleaved, thefluorochrome is released. The inhibition of the fluorochrome release isthen analysed and quantified by confocal microscopy analysis.

The protocol is the following: frozen sections of lesional skin (5-μmthickness) are rinsed with a washing solution (2% Tween 20 in PBS, 2min, followed by 5 min in PBS) and incubated or not with the testedcompound and incubated at 37° C. overnight with 100 μl of BODIPY FLcasein (10 μg/ml) using the EnzChek Ultra Protease Assay kit(Invitrogen) in 100 mM Tris-Cl, pH 8, in order to visualize globalprotease activity.

To assess KLK5 and KLK7 activities, cryostat sections after incubationor not with the tested compound, are incubated in the same conditionswith 100 μl of Boc-Val-Pro-Arg-AMC or Suc-Leu-Leu-Val-Tyr-AMC(Sigma-Aldrich) at 100 μM and 40 μM respectively in Tris 50 mM, CaCl2 10mM for the detection of trypsin- (KLK5) and chymotrypsin-like (KLK7)activity, respectively.

After incubation overnight at 37° C. with the substrate, sections arerinsed with PBS solution and visualized with the Axiovert 200 invertedhigh-end microscope (Zeiss) for KLK5 and KLK7 activities and Leica TCSSP5 AOBS for global protease activity. Images are analyzed with Image Jsoftware.

Should the coumarin derivatives inhibit KLK5 and KLK7 activities, adecrease of the release of the fluorochrome will be observed.

1. A method for the treatment of pathologies involving an excess ofactivity of at least one member of the kallikrein family, comprisingadministering to a patient in need thereof a composition comprising aneffective amount of a compound of formula (I-1) as presented below:

wherein n equals 0 or 1, and wherein if n=1, Z represents O or S, R1represents at least one group chosen among the group consisting of:hydrogen a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted, or not, by a halogen chosen among Cl, F, Iand Br, a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted by a hydroxyl or a —O—R12 group, wherein R12is a linear or branched, saturated or not, C1-C7 alkyl, preferably ahydroxyl, a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogenatom, and a linear or branched, saturated or not, C1-C7 alkyl,substituted or not by at least one halogen chosen among Cl, F, I and Br,a group —O—R13, wherein R13 is chosen among hydrogen and a linear orbranched, saturated or not, C1-C7 alkyl, R13 being preferably ahydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, and a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that when n=0, then R1can only represent a linear or branched, saturated or not, C1-C7 alkyl,preferably a methyl group, possibly substituted by an halogen, such thatif R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a methyl groupor a cycloalkyl group, preferably a cyclohexyl group, when n=1, if R1=H,then R2 can only represent an isoquinolinyl or a naphthyl, or a phenylsubstituted by two halogens, and if R1≠H, then if R2 is an aryldifferent from a naphthyl, or an hetero aryl, substituted by one linearor branched, saturated or not, C1-C7 alkyl, said aryl or heteroaryl isalso substituted by at least another group different from a C1-C7 alkyl.2. The method according to claim 1, wherein said pathologies belong tothe group consisting of Netherton syndrome, psoriasis, atopic eczema andallergic contact dermatitis.
 3. The method according to claim 1, whereinsaid at the member of the kallikrein family is chosen among the groupconsisting of kallikrein-5, kallikrein-7 and kallikrein-14.
 4. Themethod according to claim 1, said compound having the following formula(Ia):

wherein R1 represents a linear or branched, saturated or not, C1-C7alkyl, preferably a methyl group, possibly substituted by a halogen, andR2 represents a methyl group, a cycloalkyl or an aryl group, preferablya cyclohexyl or a phenyl group. said compound being in particular:


5. The method according to claim 1, wherein said compound has thefollowing formula (I-1b):

wherein Z represents O or S, R1 represents at least one group chosenamong the group consisting of: a Hydrogen a linear or branched,saturated or not, C1-C7 alkyl, preferably a methyl group, substituted,or not, by a halogen chosen among Cl, F, I and Br, a linear or branched,saturated or not, C1-C7 alkyl, preferably a methyl group, substituted bya hydroxyl or a —O—R12 group, wherein R12 is a linear or branched,saturated or not, C1-C7 alkyl, preferably a hydroxyl, a group—CH₂—O—CO—R5, wherein R5 is chosen among a hydrogen atom and a linear orbranched, saturated or not, C1-C7 alkyl, substituted or not by at leastone halogen chosen among Cl, F, I and Br, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,Cl-05 alkyl, and a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that if R1=H, then R2 canonly represent an isoquinolinyl or a naphthyl, or a phenyl substitutedby two halogens, and if R1≠H, if R2 is an aryl different from anaphthyl, or an hetero aryl, substituted by one a linear or branched,saturated or not, C1-C7 alkyl, said aryl or heteroaryl is alsosubstituted by at least another group different from a C1-C7 alkyl. saidcompound belonging in particular to the group consisting of:


6. The method according to claim 1, said compound having the followingformula (II):

wherein R1 represents: an hydrogen, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, —CH₂—Cl, —CH₂—Br, —CH₂—F,—CH₂OCOC₂H₅, or a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, and R2represents a pyridyl substituted by a Cl, or a phenyl substituted, ornot, either by a group —OCH₃ or by one or two halogens chosen among Cl,Br, F or I, a naphthyl substituted, or not, either by a group —OCH₃ orby one or two halogens chosen among Cl, Br, F or I, providing that: atleast one of R9 and R10 represents —CO—R5 or —SO₂—R11, preferably R9being —CO—R5 and R10 being hydrogen or R9 being —SO₂—R11 and R10 beinghydrogen, if R1=H, R2 can only represent a naphthyl. said compoundsbeing in particular chosen among the group consisting of:


7. The method according to claim 1, said compound having the followingformula (II):

wherein R1 represents —CH₂—Cl, —CH₂—Br, —CH₂—F, —CH₂OCOCH₃, —CH₃,—CH₂—NH₂, and its salts thereof, or H, and R2 represents: anisoquinolinyl, or —CH₃, or a pyridyl, or a phenyl, substituted or not bya halogen, provided that if R1=H, R2 can only represent anisoquinolinyl, and if R1=CH₃, R2 can only represent a CH₃. saidcompounds being in particular chosen among the group consisting of:


8. The method according to claim 1, said compound having the followingformula (II):

wherein R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃, —CH₂Cl, —CH₂—Br or—CH₂—F, and R2 represents a pyridyl or a phenyl, said pyridyl or phenylbeing mono or bisubstituted by one or two groups chosen among a halogen,an amide, an acid, a —CH₃, a —NO₂ or a —CN. said compounds being inparticular chosen among the group consisting of:


9. The method according to claim 1, said compound having the followingformula (Ib):

wherein Z represents O or S, R1 represents —CH₂Cl or —CH₂—NH₂ or itssalt thereof, and R2 represents a pyridyl or a phenyl, said pyridyl orphenyl being substituted or not by one or two halogens, one amide or oneester. said compounds being in particular chosen among the groupconsisting of:


10. The method according to claim 1, said compound having the followingformula (I-1):

wherein n equals 0 or 1, and wherein if n=1, Z represents O or S, R1represents at least one group chosen among the group consisting of:Hydrogen a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted, or not, by a halogen chosen among Cl, F, Iand Br, a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted by a hydroxyl or a —O—R12 group, wherein R12is a linear or branched, saturated or not, C1-C7 alkyl, preferably ahydroxyl, a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogenatom, and a linear or branched, saturated or not, C1-C7 alkyl,substituted or not by at least one halogen chosen among Cl, F, I and Br,a group —O—R13, wherein R13 is chosen among hydrogen and a linear orbranched, saturated or not, C1-C7 alkyl, R13 being preferably ahydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that when n=0, then R1can only represent a linear or branched, saturated or not, C1-C7 alkyl,preferably a methyl group, possibly substituted by an halogen, such thatif R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a methyl groupor a when n=1, if R1=H, then R2 can only represent an isoquinolinyl or anaphthyl, or a phenyl substituted by two halogens, and if R1≠H, then ifR2 is an aryl different from a naphthyl, or an hetero aryl, substitutedby one linear or branched, saturated or not, C1-C7 alkyl, said aryl orheteroaryl is also substituted by at least another group different froma C1-C7 alkyl, said pathologies being Netherton syndrome.
 11. The methodaccording to claim 1, said compound having the following formula (I-1b):

wherein Z represents O or S, R1 represents at least one group chosenamong the group consisting of: a linear or branched, saturated or not,C1-C7 alkyl, preferably a methyl group, substituted by a hydroxyl or a—O—R12 group, wherein R12 is a linear or branched, saturated or not,C1-C7 alkyl, preferably a hydroxyl, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that: if R2 is an aryldifferent from a naphthyl, or an hetero aryl, substituted by one alinear or branched, saturated or not, C1-C7 alkyl, said aryl orheteroaryl is also substituted by at least another group different froma C1-C7 alkyl, if R1 represents a group

 wherein R9 and R10 are independently chosen among hydrogen and a linearor branched, saturated or not, C1-C5 alkyl, or a salt thereof, R2 isdifferent from a pyridyl, and represents in particular a phenyl, saidpathologies belonging to the group consisting of psoriasis, atopiceczema and allergic contact dermatitis.
 12. The method according toclaim 3, said compound having the following formula (II):

wherein R1 represents: an hydrogen, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, —CH₂—Cl, —CH₂—Br, —CH₂—F,—CH₂OCOC₂H₅, or a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, and R2represents a pyridyl substituted by a Cl, or a phenyl substituted, ornot, either by a group —OCH₃ or by one or two halogens chosen among Cl,Br, F or I, a naphthyl substituted, or not, either by a group —OCH₃ orby one or two halogens chosen among Cl, Br, F or I, providing that: atleast one of R9 and R10 represents —CO—R5 or —SO₂—R11, preferably R9being —CO—R5 and R10 being hydrogen or R9 being —SO₂—R11 and R10 beinghydrogen, if R1=H, R2 can only represent a naphthyl. said compoundsbeing in particular chosen among the group consisting of:


13. The method according to claim 5, said compound having the followingformula (II):

wherein R1 represents: an hydrogen, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, —CH₂—Cl, —CH₂—Br, —CH₂—F,—CH₂OCOC₂H₅, or a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, and R2represents a pyridyl substituted by a Cl, or a phenyl substituted, ornot, either by a group —OCH₃ or by one or two halogens chosen among Cl,Br, F or I, a naphthyl substituted, or not, either by a group —OCH₃ orby one or two halogens chosen among Cl, Br, F or I, providing that: atleast one of R9 and R10 represents —CO—R5 or —SO₂—R11, preferably R9being —CO—R5 and R10 being hydrogen or R9 being —SO₂—R11 and R10 beinghydrogen, if R1=H, R2 can only represent a naphthyl. said compoundsbeing in particular chosen among the group consisting of:


14. The method according to claim 3, said compound having the followingformula (II):

wherein R1 represents —CH₂—Cl, —CH₂—Br, —CH₂—F, —CH₂OCOCH₃, —CH₃,—CH₂—NH₂, and its salts thereof, or H, and R2 represents: anisoquinolinyl, or —CH₃, or a pyridyl, or a phenyl, substituted or not bya halogen, provided that if R1=H, R2 can only represent anisoquinolinyl, and if R1=CH₃, R2 can only represent a CH₃. saidcompounds being in particular chosen among the group consisting of:


15. The method according to claim 5, said compound having the followingformula (II):

wherein R1 represents —CH₂—Cl, —CH₂—Br, —CH₂—F, —CH₂OCOCH₃, —CH₃,—CH₂—NH₂, and its salts thereof, or H, and R2 represents: anisoquinolinyl, or —CH₃, or a pyridyl, or a phenyl, substituted or not bya halogen, provided that if R1=H, R2 can only represent anisoquinolinyl, and if R1=CH₃, R2 can only represent a CH₃. saidcompounds being in particular chosen among the group consisting of:


16. The method according to claim 3, said compound having the followingformula (II):

wherein R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃, —CH₂Cl, —CH₂—Br or—CH₂—F, and R2 represents a pyridyl or a phenyl, said pyridyl or phenylbeing mono or bisubstituted by one or two groups chosen among a halogen,an amide, an acid, a —CH₃, a —NO₂ or a —CN. said compounds being inparticular chosen among the group consisting of:


17. The method according to claim 5, said compound having the followingformula (II):

wherein R1 represents —CH₂OCOC(CH₃)₃, —CH₂OCOCH₃, —CH₂Cl, —CH₂—Br or—CH₂—F, and R2 represents a pyridyl or a phenyl, said pyridyl or phenylbeing mono or bisubstituted by one or two groups chosen among a halogen,an amide, an acid, a —CH₃, a —NO₂ or a —CN. said compounds being inparticular chosen among the group consisting of:


18. The method according to claim 3, said compound having the followingformula (I-1):

wherein n equals 0 or 1, and wherein if n=1, Z represents O or S, R1represents at least one group chosen among the group consisting of:hydrogen a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted, or not, by a halogen chosen among Cl, F, Iand Br, a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted by a hydroxyl or a —O—R12 group, wherein R12is a linear or branched, saturated or not, C1-C7 alkyl, preferably ahydroxyl, a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogenatom, and a linear or branched, saturated or not, C1-C7 alkyl,substituted or not by at least one halogen chosen among Cl, F, I and Br,a group —O—R13, wherein R13 is chosen among hydrogen and a linear orbranched, saturated or not, C1-C7 alkyl, R13 being preferably ahydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that when n=0, then R1can only represent a linear or branched, saturated or not, C1-C7 alkyl,preferably a methyl group, possibly substituted by an halogen, such thatif R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a methyl groupor a cycloalkyl group, preferably a cyclohexyl group, when n=1, if R1=H,then R2 can only represent an isoquinolinyl or a naphthyl, or a phenylsubstituted by two halogens, and if R1≠H, then if R2 is an aryldifferent from a naphthyl, or an hetero aryl, substituted by one linearor branched, saturated or not, C1-C7 alkyl, said aryl or heteroaryl isalso substituted by at least another group different from a C1-C7 alkyl,said pathologies being Netherton syndrome.
 19. The method according toclaim 5, said compound having the following formula (I-1):

wherein n equals 0 or 1, and wherein if n=1, Z represents O or S, R1represents at least one group chosen among the group consisting of:hydrogen a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted, or not, by a halogen chosen among Cl, F, Iand Br, a linear or branched, saturated or not, C1-C7 alkyl, preferablya methyl group, substituted by a hydroxyl or a —O—R12 group, wherein R12is a linear or branched, saturated or not, C1-C7 alkyl, preferably ahydroxyl, a group —CH₂—O—CO—R5, wherein R5 is chosen among a hydrogenatom, and a linear or branched, saturated or not, C1-C7 alkyl,substituted or not by at least one halogen chosen among Cl, F, I and Br,a group —O—R13, wherein R13 is chosen among hydrogen and a linear orbranched, saturated or not, C1-C7 alkyl, R13 being preferably ahydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that when n=0, then R1can only represent a linear or branched, saturated or not, C1-C7 alkyl,preferably a methyl group, possibly substituted by an halogen, such thatif R1=CH₃ or CH₂—X, wherein X is an halogen, then R2 is a methyl groupor a cycloalkyl group, preferably a cyclohexyl group, when n=1, if R1=H,then R2 can only represent an isoquinolinyl or a naphthyl, or a phenylsubstituted by two halogens, and if R1≠H, then if R2 is an aryldifferent from a naphthyl, or an hetero aryl, substituted by one linearor branched, saturated or not, C1-C7 alkyl, said aryl or heteroaryl isalso substituted by at least another group different from a C1-C7 alkyl,said pathologies being Netherton syndrome.
 20. The method according toclaim 3, said compound having the following formula (I-1b):

wherein Z represents O or S, R1 represents at least one group chosenamong the group consisting of: a linear or branched, saturated or not,C1-C7 alkyl, preferably a methyl group, substituted by a hydroxyl or a—O—R12 group, wherein R12 is a linear or branched, saturated or not,C1-C7 alkyl, preferably a hydroxyl, a group —O—R13, wherein R13 ischosen among hydrogen and a linear or branched, saturated or not, C1-C7alkyl, R13 being preferably a hydrogen, an amine

 or a salt thereof, wherein R3 and R4, independently from each other,are chosen among hydrogen and a linear or branched, saturated or not,C1-C5 alkyl, a group

 or a salt thereof, wherein R9 and R10, independently from each other,are chosen among: hydrogen, a linear or branched, saturated or not,C1-C5 alkyl, —CO—R5, wherein R5 is chosen among a hydrogen atom, and alinear or branched, saturated or not, C1-C7 alkyl, substituted or not byat least one halogen chosen among Cl, F, I and Br, —SO₂—R11, wherein R11is a linear or branched, saturated or not, C1-C7 alkyl, R′1 represents agroup chosen among hydrogen and —O—R14, wherein R14 is chosen amonghydrogen and a linear or branched, saturated or not, C1-C7 alkyl, R14being preferably a hydrogen, R′1 being preferably a hydrogen, providedthat R′1 represents hydrogen when R1 does not represent a —O—R13 group,and R2 is chosen among the group consisting of: a linear or branched,saturated or not, C1-C7 alkyl, preferably a C1-C3 alkyl, a C3-C6cycloalkyl, preferably a C4-C6 cycloalkyl, more preferably a cyclohexyl,an aryl group, preferably a phenyl or a naphthyl group, possibly mono orpolysubstituted, in particular disubstituted, by a halogen chosen amongCl, F, I and Br, or a linear or branched, saturated or not, C1-C7 alkyl,or a group —CO—R6, R6 being chosen among the group consisting of: —OH,—NH₂, or salt thereof, and —O—R7, R7 being a linear or branched,saturated or not, C1-C7 alkyl, or a group —O—R8, R8 being a linear orbranched, saturated or not, C1-C7 alkyl, or a group —NO₂, a group —CN, acombination of the above, and an heteroaryl group, preferably a pyridylor an isoquinolinyl, possibly mono or polysubstituted, in particulardisubstituted, by a halogen chosen among Cl, F, I and Br, or a linear orbranched, saturated or not, C1-C7 alkyl, or a group —CO—R6, R6 beingchosen among the group consisting of: —OH, —NH₂, or salt thereof, and—O—R7, R7 being a linear or branched, saturated or not, C1-C7 alkyl, ora group —O—R8, R8 being a linear or branched, saturated or not, C1-C7alkyl, or a combination of the above, provided that: if R2 is an aryldifferent from a naphthyl, or an hetero aryl, substituted by one alinear or branched, saturated or not, C1-C7 alkyl, said aryl orheteroaryl is also substituted by at least another group different froma C1-C7 alkyl, if R1 represents a group

 wherein R9 and R10 are independently chosen among hydrogen and a linearor branched, saturated or not, C1-C5 alkyl, or a salt thereof, R2 isdifferent from a pyridyl, and represents in particular a phenyl, saidpathologies belonging to the group consisting of psoriasis, atopiceczema and allergic contact dermatitis.